GM-CSF stimulates osteoclastogenesis: therapeutic caution is required

Patients with a variety of tumors, including those with breast cancer, are often treated with granulocyte-monocyte colony stimulating factor (GM-CSF), a cytokine that increases white cell counts. GM-CSF stimulates the proliferation and differentiation of hematopoietic precursors, thereby replenishing blood cells ravaged by chemotherapy.

In a recent study, Park et al. [1] raise cautions about using GM-CSF in patients with breast cancer. In animal models, they show that GM-CSF promotes breast cancer metastases that destroy bone. They report that human breast cancer cells that are metastatic to bone have increased NF-kappa B signaling that results in the production of high levels of GM-CSF. GM-CSF in turn induces osteoclast formation and bone destruction. Blocking GM-CSF production or activity decreased osteoclasts growth and osteoclastic bone destruction in an animal model of breast cancer. Other NF- kappa B¿regulated genes that induce osteoclast formation, such as genes encoding IL-8 or IL-6, were also expressed by the breast cancer cells.

Since GM-CSF can increase osteoclast formation, the authors asked whether GM-CSF expression might be driving metastasis. They confirmed that GM-CSF induced osteoclast formation in human bone marrow cultures and that transfecting breast cancer cells with a super-repressor of NF-kappa B decreased the capacity of these breast cancer cells to metastasize to bone. Importantly, they showed that transfecting breast cancer cell lines that normally do not metastasize to bone with a GM-CSF expression vector increased their bone-metastatic potential. It is likely that other factors also produced by breast cancer cells, such as RANKL, IL-8 or PTHrP, are providing the differentiation stimulus required for GM-CSF to increase osteoclast formation and bone metastasis [2].

Further studies should help to determine whether administering GM-CSF to breast cancer patients puts them at risk. These new findings suggest that GM-CSF should be added to the list of factors involved in breast cancer bone metastasis and that GM-CSF may represent a new therapeutic target for such metastasis.

1. Park BK et al. Nature Med. 2007;13:62-69.
2. Roodman GD. Nature Med. 2007;13:25-26.